Chronic allograft vasculopathy (CAV), or graft arterial lumen occlusion through intima expansion, is a major cause of late heart transplant failure and patient morbidity/mortality. The etiology of CAV is multi-factonal, but involves promotion by IFN-y secreting T helper (Th) Type-1 cells. IL-33 and its receptor, ST2 are associated with the promotion of Type-2 (Th2) responses that have been proposed to support allograft survival. We find that IL-33 administration prolongs survival of fully-MHC mismatched, mouse heterotopic heart allografts. However, we demonstrate that IL-33, in addition to supporting Th2 responses, is a facilitator of myeloid antigen presenting cells (APC), which increase regulatory T cells (Treg), potent immunosuppressive cells directly implicated in tolerance. Specifically, we demonstrate that IL-33 administration increases both immature myeloid DC (mDC) and myeloid-derived suppressor cells (MDSC) that display the capacity to increase Treg during their interaction with allogeneic CD4+ T cell populations. None-the-less, we also find that ST2 is highly upregulated in rejecting allografts where, with IL-33, it may inhibit activation of cardiac endothelial cells (EC). In total, our findings support the capacity of IL-33, acting through ST2 on immune and cardiac cells, to facilitate allograft survival and potentially limit CAV. Our central and unifying hypothesis is that following heart transplantation, IL-33 promotes allograft survival by both generating myeloid APC that mediate Th2 cell polarization and Treg expansion, as well as through the direct protective effects on ST2 expressing cells ofthe allograft. In AIM I, we will determine how specific IL-33-induced genes and signaling pathways mediate the capacity of IL-33-exposed mDC to promote Th2 response and Treg in vitro and in vivo. In AIM II, we will determine the mechanisms by which IL-33-expanded immunoregulatory myeloid cells, including mDC and MDSC, facilitate allograft survival. In AIM III, we will dissect immune versus non-immune contributions to the cardiac protective capacity of ST2 and IL-33 in acute and chronic allograft rejection.